The present invention provides aqueous sustained-release pharmaceutical formulations of therapeutic proteins containing carboxymethyl ether cellulose polymer and their method of manufacture. The present invention also provides methods to use the pharmaceutical formulations that provide a variety of new benefits, including greater efficacy, safety, patient convenience, and patient compliance.
Due to recent advances in genetic and cell engineering technologies, proteins known to exhibit various pharmacological actions in vivo are capable of production in large amounts for pharmaceutical applications. A major limitation of the development of protein therapeutics is the preparation of stable pharmaceutical formulations of the proteins. Therapeutic proteins are typically administered by frequent injection because the active agent protein generally has short in vivo half-lives and negligible oral bio-availability, thus posing a significant physical burden on the patient and associated administrative costs. As such, there is currently a great deal of interest in developing and evaluating sustained-release formulations. Effective sustained-release formulations can provide a means of controlling blood levels of the active ingredient, and also provide greater efficacy, safety, patient convenience and patient compliance.
To date there have been mainly two mechanisms to achieve sustained-release of a protein therapeutic: 1) modifying the protein to increase the half-life of the protein, typically by reducing the clearance rate; and 2) preparing sustained-release formulations of protein encapsulated in polymer microspheres. The advantage to generating sustained release formulations is that the formulation could theoretically be utilized for many protein therapeutics.
Examples of polymer microsphere sustained release formulations are described in PCT publication WO 99/15154 (Tracy et al.), U.S. Pat. Nos. 5,674,534 and 5,716,644 (both to Zale et al.), PCT publication WO 96/40073 (Zale et al.), and PCT publication WO 00/38651 (Shah et al.).
U.S. Pat. Nos. 5,674,534 and 5,716,644 and PCT publication WO 96/40073 describe a polymeric matrix containing particles of erythropoietin that are stabilized against aggregation with a salt.
Unfortunately, the instability of most proteins (e.g. denaturation and loss of bioactivity upon exposure to heat, organic solvents, etc.) has greatly limited the development and evaluation of sustained-release formulations thereof. In addition these techniques are not as broadly applicable as generally anticipated due to the biochemical variability in protein that greatly influences any individual protein tolerance for the conditions required to produce microspheres.
PCT publication WO 00/38651 describes a pharmaceutical composition containing a protein in a polymeric matrix that has thermally and pH responsive gelation/de-gelation properties. These formulations may be prepared without exposure to heat or organic solvents, but are characterized by their use of modified hydrogels. The use of thermostable hydrogels suffers by undesirable difficulties of manufacture and thus is currently commercially impractical. Another undesirable characteristic of these modified hydrogels is that their biocompatibility or immunogenicity is poorly characterized.
U.S. Pat. No. 4,717,717 to A. L. Finkenaur describes compositions of epidermal growth factor that are stabilized against loss of biological activity by the presence of a cellulose polymer. There is no description of in vivo sustained release properties of these formulations.
U.S. Pat. No. 5,457,093 to Cini et al. describes gel formulations containing growth factors used in ophthalmic and topical applications. There is no description of the use of these formulations for parenteral administration, nor is there any suggestion that these formulations would have sustained release properties in vivo.
There remains a need, therefore, for parenteral sustained-release formulations of erythropoietin that can be manufactured easily and promote the stability of active agent protein contained therein.
The present invention provides a method to prepare aqueous sustained-release pharmaceutical formulations of therapeutic proteins for parenteral administration. The present invention also provides pharmaceutical formulations for general use with proteins for parenteral administration comprising:
a) a pharmaceutically active amount of a protein;
b) a pharmaceutically acceptable pH buffering agent to provide a pH in the range of about pH 4.5 to about pH 9;
c) a tonicity agent in the concentration range of about 0 to about 125 millimolar; and
d) Sodium carboxymethyl ether cellulose in the concentration range of about 0.5% to about 7% total formula weight;
wherein the pH of the aqueous formula is about 4.5 to about pH 9.0.
A preferred formulation of the present invention provides a pharmaceutical formulation of erythropoietin comprising:
a) a pharmaceutically active amount of erythropoietin;
b) a pharmaceutically acceptable pH buffering agent to provide a pH in the range of about pH 6 to about pH 9;
c) a tonicity agent in the concentration range of about 0 to about 200 millimolar; and
d) sodium carboxymethyl ether cellulose (CMC) in the concentration range of about 0.5% to about 7% total formula weight, said CMC having a molecular weight in the range of about 50,000 daltons to about 1,000,000 daltons;
wherein the pH of the formulation is about pH 6.3 to about pH 8.3.
The present invention also provides a method to prepare aqueous sustained-release pharmaceutical formulations of erythropoietin comprising admixing an aqueous solution of a CMC polymer with a pharmaceutically active amount of EPO. The formulations of the present invention utilize CMC polymer that is primarily in a solution state rather than in a micro-particulate state.
The present invention also provides methods to use these sustained-release formulations comprising dosing regimens where the formulation is administered at a wide variety of desired intervals, including, but not limited to, thrice per two weeks, once per week, once per two weeks, once per three weeks, once monthly, once per five weeks, once per six weeks, or at any other time interval or combination of time intervals that may be desirable for the particular patient.